Association Between Myocardial Oxygenation and Fibrosis in Duchenne Muscular Dystrophy: Analysis by Rest Oxygenation-Sensitive Magnetic Resonance Imaging.

BACKGROUND: Myocardial hypoxia has been demonstrated in many cardiomyopathies and is related to development of myocardial fibrosis. However, myocardial hypoxia and its association with myocardial fibrosis are understudied in Duchenne muscular dystrophy (DMD)-associated cardiomyopathy. PURPOSE: To evaluate myocardial hypoxia by oxygenation-sensitive (OS) cardiac magnetic resonance imaging, and further explore its association with fibrosis. STUDY TYPE: Prospective. SUBJECTS: Ninety-one DMD boys (8.78 ± 2.32) and 30 healthy boys (9.07 ± 2.30). FIELD STRENGTH/SEQUENCE: 3 T, Balanced steady-state free procession, Modified Look-Locker inversion recovery sequence and Single-shot phase-sensitive inversion recovery sequence. ASSESSMENT: Cardiac MRI data, including left ventricular functional, segmental native T1, and oxygenation signal-intensity (SI) according to AHA 17-segment model, were acquired. Patients were divided into LGE+ and LGE- groups. In patients with LGE, all segments were further classified as positive or negative segments by segmentally presence/absence of LGE. STATISTICAL TESTS: Variables were compared using Student's t, Wilcoxon, Kruskal-Wallis test and one-way analysis of variance. Bivariate Pearson or Spearman correlation were calculated to determine association between oxygenation SI and native T1. Variables with P < 0.10 in the univariable analysis were included in multivariable model. Receiver operating characteristic analysis was used to assess the performance of OS in diagnosing myocardial hypoxia. RESULTS: The myocardial oxygenation SI of DMD was significantly decreased in all segments compared with normal controls, and more obvious in the LGE+ segments (0.46 ± 0.03 vs. 0.52 ± 0.03). For patients with and without LGE, myocardial oxygenation SI were significantly negatively correlated with native T1 in all segments (r = -0.23 to -0.42). The inferolateral oxygenation SI was a significant independent associator of LGE presence (adjusted OR = 0.900). DATA CONCLUSION: Myocardial hypoxia evaluated by the OS-Cardiac-MRI indeed occurs in DMD and associate with myocardial fibrosis, which might be used as a biomarker in assessing myocardial damage in DMD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping.

Objective: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, which is complex, time-consuming, and lacks clinical practicality. Therefore, in this study, optical genome mapping (OGM) is employed for the genetic diagnosis of FSHD1. Furthermore, epigenetic heterogeneity is determined from methylation analysis. Methods: Genomic DNA samples from four members of the same family were subjected to whole-exome sequencing. OGM was used to identify structural variations in D4Z4, while sodium bisulfite sequencing helped identify the methylation levels of CpG sites in a region located distally to the D4Z4 array. A multidisciplinary team collected the clinical data, and comprehensive family analyses aided in the assessment of phenotypes and genotypes. Results: Whole-exome sequencing did not reveal variants related to clinical phenotypes in the patients. OGM showed that the proband was a compound heterozygote for the 4qA allele with four and eight D4Z4 repeat units, whereas the affected younger brother had only one 4qA allele with four D4Z4 repeat units. Both the proband and her younger brother were found to display asymmetric weakness predominantly involving the facial, shoulder girdle, and upper arm muscles, whereas the younger brother had more severe clinical symptoms. The proband's father, who was found to be normal after a neurological examination, also carried the 4qA allele with eight D4Z4 repeat units. The unaffected mother exhibited 49 D4Z4 repeat units of the 4qA allele and a minor mosaic pattern with four D4Z4 repeat units of the 4qA allele. Consequently, the presence of the 4qA allele in the four D4Z4 repeat units strongly pointed to the occurrence of maternal germline mosaicism. The CpG6 methylation levels were lower in symptomatic patients compared to those in the asymptomatic parents. The older sister had lower clinical scores and ACSS and higher CpG6 methylation levels than that of her younger brother. Conclusions: In this study, two siblings with FSHD1 with phenotypically normal parents were identified by OGM. Our findings suggest that the 4qA allele of four D4Z4 repeats was inherited through maternal germline mosaicism. The clinical phenotype heterogeneity is influenced by the CpG6 methylation levels. The results of this study greatly aid in the molecular diagnosis of FSHD1 and in also understanding the clinical phenotypic variability underlying the disease.

Association of increased epicardial adipose tissue derived from cardiac magnetic resonance imaging with myocardial fibrosis in Duchenne muscular dystrophy: a clinical prediction model development and validation study in 283 participants.

Background: Epicardial adipose tissue (EAT) contributes to inflammation and fibrosis of the neighboring myocardial tissue via paracrine signaling. In this retrospective study, we investigated the abnormal changes in the amount of EAT in male children with Duchenne muscular dystrophy (DMD) using cardiac magnetic resonance (CMR) imaging. Furthermore, we constructed and validated a nomogram including EAT-related CMR imaging parameter for predicting the occurrence of myocardial fibrosis in patients with DMD. Methods: This study enrolled 283 patients with DMD and 57 healthy participants who underwent CMR acquisitions to measure the quantitative parameters of EAT, pericardial adipose tissue (PAT), paracardial adipose tissue, and subcutaneous adipose tissue. Late gadolinium enhancement (LGE) was performed to confirm myocardial fibrosis in patients with DMD. The DMD group consisted of 200 patients from institution 1 (the ratio of the training set and the internal validation set was 7:3) and 83 patients from four other institutions (the external validation set). Logistic and least absolute shrinkage and selection operator (LASSO) regression was used to select the optimal predictors and to develop and validate the nomogram model predicting LGE risk in the training set, internal validation set, and external validation set. Results: Compared with those in healthy controls, some regional EAT thicknesses, areas, and global volumes were significantly higher in patients with DMD, and 41.7% of patients with DMD showed positive LGE. These LGE-positive patients with DMD showed significantly higher EAT volume (median 23.9 mL/m3; P<0.001) and PAT volume (median 31.8 mL/m3; P<0.001) compared with the LGE-negative patients with DMD. Age [odds ratio (OR) 2.0; P<0.001], body fat percentage (OR 1.3; P<0.001), and EAT volume (OR 1.4; P<0.001) were independently associated with positive LGE in the training set. The interactive dynamic nomogram showed superior prediction performance, with a high degree of the calibration, discrimination, and clinical net benefit in the training and validation of the DMD datasets. The area under the curve (AUC) values of the nomogram in the training set, internal validation set, and external validation set were 0.95 [95% confidence interval (CI): 0.91-0.98], 0.97 (95% CI: 0.92-0.99), and 0.95 (95% CI: 0.91-0.99), respectively. Conclusions: The onset of LGE-based myocardial fibrosis was associated with EAT volume in patients with DMD. Additionally, the nomogram with EAT volumes showed superior performance in patients with DMD for predicting the occurrence of myocardial fibrosis.

Altered dynamic functional and effective connectivity in drug-naive children with Tourette syndrome.

Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by repetitive, stereotyped, involuntary tics, the neurological basis of which remains unclear. Although traditional resting-state MRI (rfMRI) studies have identified abnormal static functional connectivity (FC) in patients with TS, dynamic FC (dFC) remains relatively unexplored. The rfMRI data of 54 children with TS and 46 typically developing children (TDC) were analyzed using group independent component analysis to obtain independent components (ICs), and a sliding-window approach to generate dFC matrices. All dFC matrices were clustered into two reoccurring states, the state transition metrics were obtained. We conducted Granger causality and nodal topological analyses to further investigate the brain regions that may play the most important roles in driving whole-brain switching between different states. We found that children with TS spent more time in state 2 (PFDR < 0.001), a state characterized by strong connectivity between ICs, and switched more quickly between states (PFDR = 0.025) than TDC. The default mode network (DMN) may play an important role in abnormal state transitions because the FC that changed the most between the two states was between the DMN and other networks. Additionally, the DMN had increased degree centrality, efficiency and altered causal influence on other networks. Certain alterations related to executive function (r = -0.309, P < 0.05) and tic symptom ratings (r = 0.282; 0.413, P < 0.05) may represent important aspects of the pathophysiology of TS. These findings facilitate our understanding of the neural basis for the clinical presentation of TS.

Novel implementation of cardiac magnetic resonance first-pass perfusion imaging for semi-quantitatively evaluating microvascular dysfunction in paediatric patients with Duchenne muscular dystrophy.

OBJECTIVES: The current study aimed to assess myocardial microcirculation dysfunction via cardiac magnetic resonance (CMR) first-pass perfusion imaging in children with Duchenne muscular dystrophy (DMD). METHODS: In total, 67 children with DMD and 15 controls who underwent contrast-enhanced CMR first-pass perfusion imaging were enrolled in this study. CMR first-pass perfusion and late gadolinium enhancement (LGE) sequences were acquired. Further, the global, regional, and coronary artery distribution area perfusion indexes (PI), upslope (%BL), maximum signal intensity (MaxSI), time to maximum signal intensity (TTM), and baseline SI were analysed. The perfusion parameters of the LGE positive (+), LGE negative (-), and control groups were compared. Pearson correlation analysis was performed to assess the association between myocardial microcirculation and conventional cardiac function and LGE parameters. RESULTS: The LGE+ group had a significantly lower global and apical-ventricular MaxSI than the control group (all P < .05). The left anterior descending arterial (LAD), left circumflex coronary arterial (LCX), and right coronary arterial (RCA) segments of the LGE+ group had a lower upslope and MaxSI than those of the control group (all P < .05). The LAD segments of the LGE- group had a lower MaxSI than those of the control group (41.10 ± 11.08 vs 46.36 ± 13.04; P < .001). The LCX segments of the LGE- group had a lower PI and upslope than those of the control group (11.05 ± 2.84 vs 12.46 ± 2.82; P = .001; 59.31 ± 26.76 vs 68.57 ± 29.99; P = .002). Based on the correlation analysis, the upslope, MaxSI, and TTM were correlated with conventional cardiac function and LGE extent. CONCLUSIONS: Paediatric patients with DMD may present with microvascular dysfunction. This condition may appear before LGE and may be correlated with coronary artery blood supply and LGE extent. ADVANCES IN KNOWLEDGE: First-pass perfusion parameters may reveal the status of myocardial microcirculation and reflect the degree of myocardial injury at an earlier time in DMD patients. Perfusion parameters should be analysed not only via global or base, middle, and apical segments but also according to coronary artery distribution area, which may detect myocardial microvascular dysfunction at an earlier stage, in DMD patients with LGE-.

Left ventricular concentric hypertrophy with cardiac magnetic resonance imaging improves risk stratification in patients with Duchenne muscular dystrophy: a prospective cohort study.

BACKGROUND: The development of left ventricular (LV) remodeling has been associated with an increased cardiovascular risk and cardiogenic death, and different patterns of remodeling result in varying levels of prognosis. OBJECTIVE: To investigate the association between different patterns of LV remodeling and clinical outcomes in the preclinical stage of patients with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: A total of 148 patients with DMD and 43 sex- and age-matched healthy participants were enrolled. We used the four-quadrant analysis method to investigate LV remodeling based on cardiac magnetic resonance (MR) imaging. Kaplan-Meier curves were generated to illustrate the event-free survival probability stratified by the LV remodeling pattern. Cox regression models were constructed and compared to evaluate the incremental predictive value of the LV remodeling pattern. RESULTS: During the median follow-up period of 2.2 years, all-cause death, cardiomyopathy, and ventricular arrhythmia occurred in 5, 35, and 7 patients, respectively. LV concentric hypertrophy (hazard ratio 2.91, 95% confidence interval 1.47-5.75, P=0.002) was an independent predictor of composite endpoint events. Compared to the model without LV concentric hypertrophy, the model with LV concentric hypertrophy had significant incremental predictive value (chi-square value 33.5 vs. 25.2, P=0.004). CONCLUSION: Age and late gadolinium enhancement positivity were positively correlated with clinical outcomes according to the prediction models. LV concentric hypertrophy was also an independent predictor for risk stratification and provided incremental value for predicting clinical outcomes in the preclinical stage of patients with DMD.

Different bone health progression patterns and early-stage risk marker in glucocorticoid-treated ambulatory Duchenne muscular dystrophy.

Fractures often cause irreversible harm in Duchenne muscular dystrophy (DMD). This study investigated the trajectory of bone mineral density (BMD) using group-based trajectory modeling and identified that BMD acts as an early-stage indicator of clinically significant bone fragility. The greater the early-stage BMD, the better the 4-year bone health outcome. PURPOSE: Most Duchenne muscular dystrophy (DMD) children suffer bone loss after long-term glucocorticoid (GC) exposure, which induces scoliosis and fragility fractures. To assess the BMD progression pattern and individual medical risk markers for these phenotypes in young ambulatory boys with DMD, and provide evidence-based suggestions for clinical management of bone health. METHODS: A retrospective longitudinal cohort study of 153 boys with DMD in West China Second University Hospital (2016-2023) was performed. Group-based trajectory modeling was used to study the BMD progression pattern, and potential predictors were further analyzed by logistic regression and survival analysis. RESULTS: One hundred and fifty-three participants were included, 71 of which had more than 3 BMD records. Three BMD trajectories were identified. Baseline BMD and age-started GC and were independent predictors of trajectory attribution. The median survival time of the first observation of low BMD in GC-treated DMD boys was 5.32 (95% CI 4.05-6.59) years, and a significant difference was tested (P < 0.001) among the three trajectory groups. CONCLUSION: BMD may serve as a novel early indicating marker for monitoring bone fragility for DMD. We proposed a bone health risk stratification through BMD progression trajectory that allows us to adapt the osteoporosis warning sign in DMD from a fixed threshold approach to a more individualized strategy, where baseline BMD and age of glucocorticoid initiation can provide an earlier prediction of bone loss. Better management of primary BMD may be able to delay or avoid the onset of adverse bone health outcomes in the fifth year in children with DMD.

Derivation and validation of diagnostic models for myocardial fibrosis in duchenne muscular dystrophy: assessed by multi-parameter cardiovascular magnetic resonance.

BACKGROUND: Gadolinium-enhanced cardiovascular magnetic resonance (CMR) is the most widely used approach for diagnosing myocardial fibrosis with late gadolinium enhancement (LGE) in cardiomyopathy associated with Duchenne muscular dystrophy. Given the limitations and safety of gadolinium use, we wanted to develop and evaluate multi-parametric pre-contrast CMR models for the diagnosis of LGE and investigate whether they could be utilised as surrogates for LGE in DMD patients. METHODS: A total of 136 DMD patients were prospectively recruited and separated into LGE - and LGE + groups. In the first subset of patients (derivation cohort), regression models for the diagnosis of LGE were built by logistic regression using pre-contrast sequence parameters. In a validation cohort of other patients, the models' performances were evaluated. RESULTS: EF, native T1 and longitudinal strain alone, as well as their combinations form seven models. The model that included EF, native T1 and longitudinal strain had the best diagnostic value, but there was no significant difference in diagnostic accuracy among the other models except EF. In the validation cohort, the diagnosis outcomes of models were moderate consistent with the existence of LGE. The longitudinal strain outperformed the other models in terms of diagnostic value (sensitivity: 83.33%, specificity: 54.55%). CONCLUSIONS: Pre-contrast sequences have a moderate predictive value for LGE. Thus, pre-contrast parameters may be considered only in a specific subset of DMD patients who cannot cooperate for long-time examinations and have contradiction of contrast agent to help predict the presence of LGE. TRIAL REGISTRATION NUMBER (TRN): ChiCTR1800018340 DATE OF REGISTRATION: 20180107.

Case report: Analysis of a gene variant and prenatal diagnosis in a family with megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited cerebral white matter disorder in children. Pathogenic variations in the causative gene MLC1 are found in approximately 76% of patients and are inherited in an autosomal recessive manner. In this study, we identified an IVS2 + 1delG variant in MLC1 in the firstborn girl of a pregnant woman who has the clinical features of MLC, including macrocephaly, motor development delay, progressive functional deterioration, and myelinopathy, whereas no obvious subcortical cysts were observed by magnetic resonance imaging of the brain. The proband is homozygous for the IVS2 + 1delG mutation, which was inherited from the parents. This variant disrupts the donor splice site, causing an abnormal transcript that results in a premature termination codon and produces a truncated protein, which was confirmed to affect splicing by MLC1 cDNA analysis. This variant was also detected in family members, and a prenatal diagnosis for the fetus was undertaken. Eventually, the couple gave birth to an unaffected baby. Furthermore, we conducted a long-term follow-up of the proband's clinical course. This report improves our understanding of the genetic and phenotypic characteristics of MLC and provides a new genetic basis for prenatal diagnosis and genetic counseling.

Longitudinal changes in magnetic resonance imaging biomarkers of the gluteal muscle groups and functional ability in Duchenne muscular dystrophy: a 12-month cohort study.

BACKGROUND: Quantitative magnetic resonance imaging (MRI) is considered an objective biomarker of Duchenne muscular dystrophy (DMD), but the longitudinal progression of MRI biomarkers in gluteal muscle groups and their predictive value for future motor function have not been described. OBJECTIVE: To explore MRI biomarkers of the gluteal muscle groups as predictors of motor function decline in DMD by characterizing the progression over 12 months. MATERIALS AND METHODS: A total of 112 participants with DMD were enrolled and underwent MRI examination of the gluteal muscles to determine fat fraction and longitudinal relaxation time (T1). Investigations were based on gluteal muscle groups including flexors, extensors, adductors, and abductors. The North Star Ambulatory Assessment and timed functional tests were performed. All participants returned for follow-up at an average of 12 months and were divided into two subgroups (functional stability/decline groups) based on changes in timed functional tests. Univariable and multivariable logistic regression methods were used to explore the risk factors associated with future motor function decline. RESULTS: For the functional decline group, all T1 values decreased, while fat fraction values increased significantly over 12 months (P<0.05). For the functional stability group, only the fat fraction of the flexors and abductors increased significantly over 12 months (P<0.05). The baseline T1 value was positively correlated with North Star Ambulatory Assessment and negatively correlated with timed functional tests at the 12-month follow-up (P<0.001), while the baseline fat fraction value was negatively correlated with North Star Ambulatory Assessment and positively correlated with timed functional tests at the 12-month follow-up (P<0.001). Multivariate regression showed that increased fat fraction of the abductors was associated with future motor function decline (model 1: odds ratio [OR]=1.104, 95% confidence interval [CI]: 1.026~1.187, P=0.008; model 2: OR=1.085, 95% CI: 1.013~1.161, P=0.019), with an area under the curve of 0.874. CONCLUSION: Fat fraction of the abductors is a powerful predictor of future motor functional decline in DMD patients at 12 months, underscoring the importance of focusing early on this parameter in patients with DMD.

Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence.

Pontocerebellar hypoplasia type 8(PCH8) is a rare neurodegenerative disorder, reportedly caused by pathogenic variants of the CHMP1A in autosomal recessive inheritance, and CHMP1A variants have also been implicated in other diseases, and yet none of the prenatal fetal features were reported in PCH8. In this study, we investigated the phenotype and genotype in a human subject with global developmental delay, including clinical data from the prenatal stage through early childhood. Prenatally, the mother had polyhydramnios, and the bilateral ventricles of the fetus were slightly widened. Postnatally, the infant was observed to have severely delayed psychomotor development and was incapable of visual tracking before 2 years old and could not fix on small objects. The young child had hypotonia, increased knee tendon reflex, as well as skeletal malformations, and dental crowding; she also had severe and recurrent pulmonary infections. Magnetic resonance imaging of the brain revealed a severe reduction of the cerebellum (vermis and hemispheres) and a thin corpus callosum. Through whole exome sequencing and whole genomics sequencing, we identified two novel compound heterozygous variations in CHMP1A [c.53 T > C(p.Leu18Pro)(NM_002768.5) and exon 1 deletion region (NC_000016.10:g.89656392_89674382del)]. cDNA analysis showed that the exon1 deletion region led to the impaired expression, and functional verification with zebrafish embryos using base edition indicated variant c.53 T > C (p.Leu18Pro), causing dysplasia of the cerebellum and pons. These results provide further evidence that CHMP1A variants in a recessive inheritance pattern contribute to the clinical characteristics of PCH8 and further expand our knowledge of the phenotype and genotype spectrum of PCH8.

The metabolomic plasma profile of patients with Duchenne muscular dystrophy: providing new evidence for its pathogenesis.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal genetic muscle-wasting disease that affects 1 in 5000 male births with no current cure. Despite great progress has been made in the research of DMD, its underlying pathological mechanism based on the metabolomics is still worthy of further study. Therefore, it is necessary to gain a deeper understanding of the mechanisms or pathogenesis underlying DMD, which may reveal potential therapeutic targets and/or biomarkers. RESULTS: Plasma samples from 42 patients with DMD from a natural history study and 40 age-matched healthy volunteers were subjected to a liquid chromatography-mass spectrometry-based non-targeted metabolomics approach. Acquired metabolic data were evaluated by principal component analysis, partial least squares-discriminant analysis, and metabolic pathway analysis to explore distinctive metabolic patterns in patients with DMD. Differentially expressed metabolites were identified using publicly available and integrated databases. By comparing the DMD and healthy control groups, 25 differential metabolites were detected, including amino acids, unsaturated fatty acids, carnitine, lipids, and metabolites related to the gut microbiota. Correspondingly, linoleic acid metabolism, D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, and alanine, aspartate, and glutamate metabolism were significantly altered in patients with DMD, compared with those of healthy volunteers. CONCLUSIONS: Our study demonstrated the abnormal metabolism of amino acids, energy, and lipids in patients with DMD, consistent with pathological features, such as recurrent muscle necrosis and regeneration, interstitial fibrosis, and fat replacement. Additionally, we found that metabolites of intestinal flora were disordered in DMD patients, providing support for treatment of intestinal microbia disturbance in DMD diseases. Our study provides a new research strategy for understanding the pathogenesis of DMD.

Clinical utilisation of multimodal quantitative magnetic resonance imaging in investigating muscular damage in Duchenne muscular dystrophy: a study on the association between gluteal muscle groups and motor function.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterised by progressive muscular weakness and atrophy. Currently, studies on DMD muscle function mostly focus on individual muscles; little is known regarding the effect of gluteal muscle group damage on motor function. OBJECTIVE: To explore potential imaging biomarkers of hip and pelvic muscle groups for measuring muscular fat replacement and inflammatory oedema in DMD with multimodal quantitative magnetic resonance imaging (MRI). MATERIALS AND METHODS: One hundred fifty-nine DMD boys and 32 healthy male controls were prospectively included. All subjects underwent MRI examination of the hip and pelvic muscles with T1 mapping, T2 mapping and Dixon sequences. Quantitatively measured parameters included longitudinal relaxation time (T1), transverse relaxation time (T2) and fat fraction. Investigations were all based on hip and pelvic muscle groups covering flexors, extensors, adductors and abductors. The North Star Ambulatory Assessment and stair climbing tests were used to measure motor function in DMD. RESULTS: T1 of the extensors (r = 0.720, P < 0.01), flexors (r = 0.558, P < 0.01) and abductors (r = 0.697, P < 0.001) were positively correlated with the North Star Ambulatory Assessment score. In contrast, T2 of the adductors (r = -0.711, P < 0.01) and fat fraction of the extensors (r = -0.753, P < 0.01) were negatively correlated with the North Star Ambulatory Assessment score. Among them, T1 of the abductors (b = 0.013, t = 2.052, P = 0.042), T2 of the adductors (b = -0.234, t = -2.554, P = 0.012) and fat fraction of the extensors (b = -0.637, t = - 4.096, P < 0.001) significantly affected the North Star Ambulatory Assessment score. Moreover, T1 of the abductors was highly predictive for identifying motor dysfunction in DMD, with an area under the curve of 0.925. CONCLUSION: Magnetic resonance biomarkers of hip and pelvic muscle groups (particularly T1 values of the abductor muscles) have the potential to be used as independent risk factors for motor dysfunction in DMD.

High-Speed T2 -Corrected Multiecho Magnetic Resonance Spectroscopy for Quantitatively Detecting Skeletal Muscle Fatty Infiltration and Predicting the Loss of Ambulation in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: High-speed T2 -corrected multiecho MRS (HISTO-MRS) is emerging as a quantitative modality for detecting muscle fat infiltration (MFF). However, the predictive value of HISTO-MRS for the loss of ambulation (LoA) in Duchenne muscular dystrophy (DMD) is unknown. PURPOSE: To determine the feasibility of HISTO-MRS for assessing MFF in DMD and further identify the predictive value of HISTO-MRS for the LoA. STUDY TYPE: Prospective. SUBJECTS: A total of 134 DMD boys (9.20 ± 2.43 years old) and 21 healthy boys (9.25 ± 2.10 years old). FIELD STRENGTH/SEQUENCE: A 3 T, fast spin echo T1 -weighted imaging (T1 WI), two-point-Dixon gradient echo sequence (2-pt-Dixon) and HISTO-MRS. ASSESSMENT: Subjective T1 WI fat grades by three radiologists, ROI analysis for MFF on 2 pt-Dixon (Dixon MFF) and MFF on HISTO-MRS (HISTO MFF) by two radiologists. Clinical motor function: North Star Ambulatory Assessment, 10-m run/walk time, Gowers maneuver, and time to four-stairs climb and descend. STATISTICAL TESTS: Spearman rank correlation was used to assess the relation of fat filtration assessments and motor ability. Bland-Altman plots was performed to determine the agreement of HISTO MFF and Dixon MFF. Receiver operating characteristic (ROC) curves were analyzed to determine the discriminating ability of above MRI modalities for ambulatory and nonambulatory DMD. Logistic regression was used to identify the predictor of LoA. Variables with P < 0.05 in univariate logistic regression analysis were entered into the multivariate logistic regression model. RESULTS: HISTO MFF was significantly correlated with Dixon MFF. Bland-Altman plots show good agreement of HISTO MFF and Dixon MFF. ROC curves indicated that HISTO MFF show similar discrimination of LoA for DMD with Dixon MFF but better value than T1WI fat grades. Logistic regression showed that HISTO MFF was an independent predictor for LoA. DATA CONCLUSION: HISTO-MRS is a potential quantitative method for assessing fat infiltration and shows predictive value for LoA in DMD patients. TECHNICAL EFFICACY: Stage 5.

Connectomic disturbances in Duchenne muscular dystrophy with mild cognitive impairment.

Duchenne muscular dystrophy (DMD) is frequently associated with mild cognitive deficits. However, the underlying disrupted brain connectome and the neural basis remain unclear. In our current study, 38 first-episode, treatment-naive patients with DMD and 22 matched healthy controls (HC) were enrolled and received resting-sate functional magnetic resonance imaging scans. Voxel-based degree centrality (DC), seed-based functional connectivity (FC), and clinical correlation were performed. Relative to HC, DMD patients had lower height, full Intellectual Quotients (IQ), and IQ-verbal comprehension. Significant increment of DC of DMD patients were found in the left dorsolateral prefrontal cortex (DLPFC.L) and right dorsomedial prefrontal cortex (DMPFC.R), while decreased DC were found in right cerebellum posterior lobe (CPL.R), right precentral/postcentral gyrus (Pre/Postcentral G.R). DMD patients had stronger FC in CPL.R-bilateral lingual gyrus, Pre/Postcentral G.R-Insular, and DMPFC.R-Precuneus.R, had attenuated FC in DLPFC.L-Insular. These abnormally functional couplings were closely associated with the extent of cognitive impairment, suggested an over-activation of default mode network and executive control network, and a suppression of primary sensorimotor cortex and cerebellum-visual circuit. The findings collectively suggest the distributed brain connectome disturbances maybe a neuroimaging biomarker in DMD patients with mild cognitive impairment.

Longitudinal study of multi-parameter quantitative magnetic resonance imaging in Duchenne muscular dystrophy: hyperresponsiveness of gluteus maximus and detection of subclinical disease progression in functionally stable patients.

OBJECTIVE: To describe the disease progression of Duchenne muscular dystrophy (DMD) in the pelvic and thigh muscles over 1-year using multiple-parameter quantitative magnetic resonance imaging (qMRI), and to determine the most responsive muscle and predict subclinical disease progression in functionally stable patients. METHODS: Fifty-four DMD patients (mean age 8.9 ± 2.5, range 5-15 years) completed baseline and 1-year follow-up qMRI examinations/biomarkers [3-point Dixon/fat fraction (FF); T1 mapping/T1; T2 mapping/T2]. Meanwhile, clinical assessments [NorthStar ambulatory assessment (NSAA) score] and timed function tests were performed in DMD patients. Twenty-four healthy male controls (range 5-15 years) accomplished baseline qMRI examinations. Group differences were compared using the Wilcoxon test. The standardized response mean (SRM) was taken as the responsiveness to the disease progression index. RESULTS: FF, T1, and T2 in all DMD age subgroups changed significantly over 1-year (P < 0.05). Even in functionally stable patients (NSAA score increased, unchanged, or decreased by 1-point) over 1-year, significant increases in FF and T2 and decreases in T1 were observed in gluteus maximus (GMa), gluteus medius, vastus lateralis, and adductor magnus (P < 0.05). Overall, the SRM of FF, T1, and T2 was all the highest in GMa, which were 1.25, - 0.92, and 0.93, respectively. CONCLUSIONS: qMRI biomarkers are responsive to disease progression and can also detect subclinical disease progression in functionally stable DMD patients over 1-year. GMa is the most responsive to disease progression of all the muscles analyzed. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ) ChiCTR1800018340, 09/12/2018, prospectively registered.

[Cross-Sectional Study of Nutritional Status and Dietary Nutrient Intake in Children with Duchenne Muscular Dystrophy (DMD) in China].

Objective: To investigate the dietary nutrient intake and the nutritional status of children with Duchenne muscular dystrophy (DMD), and to explore the correlation between them, so as to provide theoretical basis for the formulation of proper nutritional treatment for children with DMD. Methods: A total of 223 children aged 2 to 14 years who came to West China Second University Hospital, Sichuan University from July 2017 to April 2021, and who were diagnosed with DMD by genetic testing were enrolled as the subjects of the study. Dietary assessment was conducted with a 3-day 24-hour dietary recall, and serum vitamin D level was measured by chemiluminescence method. Results: Only 33.2% of the children with DMD were found to be of normal nutritional status. The incidences of stunted growth, underweight, overweight and obesity were 13.5%, 14.4%, 14.3% and 8.1%, respectively. Among the children with DMD, those with serum vitamin D deficiency and insufficiency accounted for 9.0% and 89.7%, respectively. According to the dietary recall of the children with MDM, the daily energy ratio of carbohydrate, protein and fat were (47.40±6.64)%, (14.46±2.22)%, and (38.17±5.30)%, respectively. The daily intake of dietary calcium and vitamin D were (433.32±164.39) mg per day and (155.73±89.30) IU per day, respectively. The ratio of daily protein intake to the estimated average requirement for protein ( P=0.003) and ratio of daily energy intake to the estimated energy requirement ( P=0.007) were lower in children with stunted growth than those of DMD children of normal nutritional status. Conclusion: The dietary structure of children with DMD is obviously not suited to their condition and nutritional deficiency coexists with overnutrition among them. Further research needs to be done for developing appropriate nutritional guidance programs and standardized nutritional management measures for children with DMD.

Utilization of T1-Mapping for the pelvic and thigh muscles in Duchenne Muscular Dystrophy: a quantitative biomarker for disease involvement and correlation with clinical assessments.

BACKGROUND: Little is known about the disease distribution and severity detected by T1-mapping in Duchenne muscular dystrophy (DMD). Furthermore, the correlation between skeletal muscle T1-values and clinical assessments is less studied. Hence, the purposes of our study are to investigate quantitative T1-mapping in detecting the degree of disease involvement by detailed analyzing the hip and thigh muscle, future exploring the predicting value of T1-mapping for the clinical status of DMD. METHODS: Ninety-two DMD patients were included. Grading fat infiltration and measuring the T1-values of 19 pelvic and thigh muscles (right side) in axial T1-weighted images (T1WI) and T1-maps, respectively, the disease distribution and severity were evaluated and compared. Clinical assessments included age, height, weight, BMI, wheelchair use, timed functional tests, NorthStar ambulatory assessment (NSAA) score, serum creatine kinase (CK) level. Correlation analysis were performed between the muscle T1-value and clinical assessments. Multiple linear regression analysis was conducted for the independent association of T1-value and motor function. RESULTS: The gluteus maximus had the lowest T1-value, and the gracilis had the highest T1-value. T1-value decreased as the grade of fat infiltration increased scored by T1WI (P < 0.001). The decreasing of T1-values was correlated with the increase of age, height, weight, wheelchair use, and timed functional tests (P < 0.05). T1-value correlated with NSAA (r = 0.232-0.721, P < 0.05) and CK (r = 0.208-0.491, P < 0.05) positively. T1-value of gluteus maximus, tensor fascia, vastus lateralis, vastus intermedius, vastus medialis, and adductor magnus was independently associated with the clinical motor function tests (P < 0.05). Interclass correlation coefficient (ICC) analysis and Bland-Altman plots showed excellent inter-rater reliability of T1-value region of interest (ROI) measurements. CONCLUSION: T1-mapping can be used as a quantitative biomarker for disease involvement, further assessing the disease severity and predicting motor function in DMD.